Aging itself is the number one risk factor for a number of chronic diseases, including cardiovascular disease, type 2 diabetes, and neurodegenerative diseases. One physiological hallmark of aging is sarcopenia or the gradual loss of skeletal muscle mass and therefore functions. While the link between aging and muscle mass loss exists across many species, the mechanism by which muscle mass loss or prevention of declining muscle function have not been completely elucidated. Similarly, many of the processes or environmental modifiers, such as dietary restriction (DR), which can protect against the aging process, are conserved from yeast to invertebrate model to vertebrate models, suggesting common molecular, biochemical, and physiological mechanisms. Thus, model organisms, such as the Drosophila Melanogaster, with complex body plans, relatively short life span, powerful genetic tools, and well defined aging phenotypes are ideally situated for the discovery of new mechanisms of aging. One well defined aging pathway is the target of rapamycin (TOR) pathway, modulation of which has been shown to extend lifespan in yeast, worms, flies and even mice. We and others have recently found that muscle specific modulation of eukaryotic translation initiation factor 4E binding protein (4E-BP), a downstream target of TOR has non-autonomous effects that can alter lifespan and triglyceride metabolism in the fat body. One potential mechanism is through the ability of muscle to secrete proteins with paracrine and endocrine actions. We hypothesize that DR/4E-BP mediate their benefits on healthspan in part through skeletal muscle secreted proteins (myokines) that have tissue specific and whole organism benefits. We also hypothesize that effects of 4E-BP on muscle are conserved between invertebrates and mammals. In order to find conserved targets of 4E-BP that are secreted in the muscle, we propose to use human muscle cells to determine the 4E-BP dependent secreted proteins from skeletal muscle. The list of candidate proteins will be compared with existing data on the 4E-BP dependent differences in translated mRNAs from fly thorax muscle. The combination of human and fly approach should lead to identification of high conserved 4E-BP dependent secreted proteins. Once these proteins have been identified they will be systemically genetically manipulated in fly skeletal muscle to determine whether they are sufficient and/or necessary for the DR/4E-BP benefits on healthspan. In additional we will examine whether manipulation of the targets in muscle is sufficient to alter fat body phenotype and whether blocking of the likely mechanism of action of the target is sufficient or necessary for the DR/4E-BP benefits on healthspan. Together we believe this is an innovative translational approach that should provide insight into highly conserved biological mechanisms important in aging and age-related chronic diseases. Furthermore, specific proteins identified may have therapeutic potential to prevent/treat a number of age related diseases. PUBLIC HEALTH RELEVANCE: Aging is a multifaceted process associated with the development of many chronic diseases. Important processes that modulate aging are conserved across invertebrate and vertebrate organisms, including increased physical activity which protects against aging potentially through a skeletal muscle specific mechanism. We propose to use a translational approach by combing Drosophila and human skeletal muscle models to screen for novel conversed secreted proteins that may play a protective role in the aging process. The mechanism of action for these conserved secreted proteins can be explored in well- established Drosophila experimental paradigms to measure muscle function, activity aging and healthspan.